It has long been believed that abnormal DNA methylation turns of tumor suppressor genes during carcinogenesis, but no biomarker or therapeutic approach has resulted. We find that abnormal de novo methylation at tumor suppressor genes is very rare, and that the dominant abnormality is a loss of DNA methylation across the genome. While demethylation in cancer has been regarded as a contributor to tumor progression, the data shown here indicate instead that is more likely to be a manifestation of a methylation-based antitumor system that induces apoptosis of tumor cells and elicits an antitumor immune response. Further investigation of genome demethylation in cancer may produce new approaches to diagnosis and treatment. Demethylation occurs early in tumorigenesis, and it may be possible to devise treatments that will augment the methylation suicide pathway so as to reduce the incidence or severity of malignant disease. The stability and sensitivity of detection of DNA biomarkers as compared to other biomolecules suggests that the identification of DNA methylation biomarkers through whole-genome methylation profiling could be effective in enhancing early diagnosis.